Inhibitory Network Plasticity in Neurological Disease

神经系统疾病中的抑制网络可塑性

• 批准号: 10382235
• 负责人: Vijayalakshmi Santhakumar
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382235
• 关键词: Adult; Affect; Axon; Behavior; Brain; Calcium; Cell physiology; Cells; Computer Models; Data; Development; Disease; Drug resistance; Epilepsy; Epileptogenesis; Experimental Models; Feedback; Genetic; Hilar; Hippocampus (Brain); Human; Image; Impairment; Injury; Interneurons; Knowledge; Label; Literature; Location; Mediating; Memory; Memory impairment; Mission; Molecular; Morphology; Mus; Myoepithelial cell; National Institute of Neurological Disorders and Stroke; Neurons; Optics; Output; Parvalbumins; Pathologic Processes; Pathway interactions; Patients; Pattern; Phase; Physiology; Pilocarpine; Play; Prevention; Regulation; Resistance; Retroviral Vector; Role; Saline; Seizures; Status Epilepticus; Structure; Supporting Cell; Synapses; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; Transgenic Mice; acquired epilepsy; comorbidity; dentate gyrus; disability; excitatory neuron; experimental study; gamma-Aminobutyric Acid; granule cell; hippocampal sclerosis; improved; memory process; molecular marker; morphometry; nervous system disorder; nestin protein; network models; neurogenesis; novel; patch sequencing; place fields; postsynaptic; preference; prevent; recruit; tool; transcriptomics

Project Summary: Temporal lobe epilepsy (TLE) develops in a third of over 300,000 patients with a first seizure and over 30% of cases are resistant to drugs contributing to a significant disability. Presence of a therapeutic time window between the initial insult and development of epilepsy suggests that improved mechanistic understanding of early pathological process may enable prevention of epileptogenesis and associated co-morbidities. While sclerosis of the hippocampal dentate gyrus characterizes late stage TLE, cell loss, network reorganization and deficient inhibition in the dentate gyrus occur soon after insults that progress to TLE. In particular, the dentate inhibitory gate which limits GC activity throughput is compromised early in acquired TLE. However, what cells and circuits make up the dentate inhibitory gate and how this is compromised after seizures is not fully understood. Recently, a new class of neurons, semilunar granule cells (SGCs) were proposed as drivers of sustained dentate feedback inhibition. Although SGC-like neuros are observed in multiple species including humans and are activated during behaviors, the development, molecular identity, and connectivity of SGCs are not known making it difficult to determine their role in dentate function and disease. The limited literature and our pilot data that SGCs input and output connections are distinct from granule cells indicating that they play a unique role in dentate processing. This study will test the hypothesis that SGCs from a parallel dentate circuit that strengthens inhibition in the normal brain. We further propose that cellular and network changes after seizures compromise SGC mediated inhibition and augment their excitatory effects contributing to epilepsy and memory deficits. Combining morphometry, Patch-seq transcriptomics, electro- and optophysiology in transgenic mouse lines subject to experimental epilepsy and computational modeling will allow us to test the above hypothesis. Aim 1 will define the cellular and circuit identity of SGCs and determine molecular markers. Aim 2 will determine if the SGC excitatory circuit is strengthened and feedback inhibitory circuit compromised after status epilepticus. Finally, Aim 3 will examine the normal and seizure-induced development of SGCs and their contribution to dentate memory processing. On completion the studies will eliminate specific knowledge gaps in how the dentate circuit functions in behaviors and epilepsy, in keeping with the NINDS mission, and provide information needed to prevent collapse of dentate inhibition soon after seizures and prevent development of epilepsy and memory co-morbidities.

颞叶癫痫（TLE）在超过30万例首次发作的患者中占三分之一。 超过30%的病例对药物有抗药性，导致严重残疾。存在 癫痫的初始损伤和发展之间的治疗时间窗表明， 对早期病理过程的机制了解可能有助于预防癫痫发生， 相关合并症。虽然海马齿状回硬化是晚期TLE的特征， 损伤后不久，齿状回出现丢失、网络重组和抑制不足， 到TLE。特别是，限制GC活性通量的齿状抑制门在早期就受到损害。 获得TLE。然而，什么样的细胞和电路构成齿状抑制门， 癫痫发作后的危害还不完全清楚。最近，一类新的神经元，半月颗粒细胞， （SGCs）被认为是持续的齿状反馈抑制的驱动因素。尽管类SGC神经元 在包括人类在内的多个物种中观察到，并在行为、发育、分子 SGCs的身份和连接性尚不清楚，这使得难以确定它们在齿状功能中的作用 和疾病有限的文献和我们的试点数据，SGCs的输入和输出连接是不同的 颗粒细胞表明它们在齿状加工中发挥着独特的作用。本研究将检验这一假设 SGCs来自一个平行的齿状回路，加强了正常大脑中的抑制作用。我们进一步建议， 癫痫发作后细胞和网络的变化削弱了SGC介导的抑制作用，并增强了它们的兴奋性。 导致癫痫和记忆缺陷。结合形态测量，Patch-seq转录组学， 转基因小鼠实验性癫痫和计算性癫痫的电生理学和光生理学 建模将使我们能够测试上述假设。目标1将定义SGCs的蜂窝和电路标识 并确定分子标记目标2将确定SGC兴奋回路是否得到加强， 癫痫持续状态后反馈抑制回路受损。最后，目标3将检查正常和 海马诱导的SGCs发育及其对齿状记忆加工的作用完成后 这些研究将消除齿状回在行为中如何发挥作用的具体知识空白， 癫痫，与NINDS使命保持一致，并提供防止齿状回塌陷所需的信息。 抑制癫痫发作后不久，并防止癫痫和记忆共病的发展。

项目成果

Fingerprints of Interictal Spikes: Can Imprints Deliver a Verdict on Their Role in Epilepsy?

发作间期尖峰的指纹：印记能否判断其在癫痫中的作用？

• DOI: 10.5698/1535-7597-16.1.41
• 发表时间: 2016
• 期刊: Epilepsy currents
• 影响因子: 3.6
• 作者: Proddutur,Archana;Santhakumar,Viji
• 通讯作者: Santhakumar,Viji

Dentate cannabinoid-sensitive interneurons undergo unique and selective strengthening of mutual synaptic inhibition in experimental epilepsy.

• DOI: 10.1016/j.nbd.2016.01.013
• 发表时间: 2016-05
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Yu J;Swietek B;Proddutur A;Santhakumar V
• 通讯作者: Santhakumar V

Seizure-induced alterations in fast-spiking basket cell GABA currents modulate frequency and coherence of gamma oscillation in network simulations.

• DOI: 10.1063/1.4830138
• 发表时间: 2013-11
• 期刊: Chaos
• 影响因子: 2.9
• 作者: Archana Proddutur;Jiandong Yu;F. Elgammal;V. Santhakumar

Distinct effect of impact rise times on immediate and early neuropathology after brain injury in juvenile rats.

• DOI: 10.1002/jnr.23401
• 发表时间: 2014-10
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Neuberger, Eric J.;Wahab, Radia Abdul;Jayakumar, Archana;Pfister, Bryan J.;Santhakumar, Vijayalakshmi
• 通讯作者: Santhakumar, Vijayalakshmi

Dentate total molecular layer interneurons mediate cannabinoid-sensitive inhibition.

• DOI: 10.1002/hipo.22419
• 发表时间: 2015-08
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Yu J;Swietek B;Proddutur A;Santhakumar V
• 通讯作者: Santhakumar V